Antidepressants reboot the brain for new experience

Babies soak up environmental stimuli and learn from them. At no later point in life is our brain as receptive and ready to develop new wiring. Neuroplasticity is the name given to this ability of the brain to adapt to stimuli, process new experiences and redistribute tasks, for instance in the event of a physical limitation or sensory impairment. At the other end of this receptivity scale one finds people with clinical depression, a disease that affects about 15 per cent of the total population at least once in the course of their lives. “These individuals are dejected, listless, as though in the grip of psychological paralysis, and some lose the will to live because of it,” is how Rupert Lanzenberger, head of the Neuroimaging Lab at the University Department of Psychiatry and Psychotherapy at the Medical University of Vienna, describes the clinical picture.

So-called SSRIs, short for selective serotonin reuptake inhibitors, are among the most commonly prescribed antidepressants. They usually take effect after a few weeks and show few side effects. There was only limited previous research about how exactly the drugs change the neurotransmitter regime and neuronal networks in the human brain. Funded by the Austrian Science Fund FWF, a double-blind study has now been conducted on healthy individuals at the Medical University of Vienna. The team of principal investigator Rupert Lanzenberger successfully used imaging techniques to show that SSRIs boost neuroplasticity and thus facilitate certain learning processes in the brain. This opens up new possibilities for launching alternative or faster-acting drugs.

Lowering the relearning threshold

The neurotransmitter serotonin is involved in determining what the brain is supposed to store or change over the course of a lifetime. Various animal studies support the theory that SSRIs lower the threshold for this process and thus increase neuroplasticity: “In principle, every conversation can change the microstructure of our brain, and serotonin modulates the degree of neuroplasticity with which the brains reacts to environmental stimuli. The adult brain no longer finds it that easy to store every new experience, which is why its neuronal microstructures do not change as quickly as they do in children and adolescents. But adults still have to react to changes, for instance when forced to take another route to work because of roadworks. We relearn by memorising a new route,” Lanzenberger explains.

In order to investigate whether antidepressants promote the relearning process compared to a placebo, Rupert Lanzenberger’s team conducted a six-week double-blind study with 80 healthy volunteers. Magnetic resonance imaging was used to measure the microstructure, the functional and structural connectivity as well as the interaction and activity of brain areas that are particularly significant for memory processes, such as the hippocampus and the insula. In addition, magnetic resonance spectroscopy was used to quantify the concentration of the most important excitatory neurotransmitter – glutamate – and the most important inhibitory neurotransmitter – gamma-aminobutyric acid – in different brain regions.

Essential mechanism of action confirmed

At the beginning of the study, a baseline examination served to measure the unaffected connectivity and activity of the relevant brain areas as well as the concentration of neurotransmitters in all test subjects. Subsequently, one group was subjected to a daily concentration task where they had to match unfamiliar faces in pairs, and the other group learned to associate Chinese characters with words. After a comparison measurement, the test subjects starting taking either SSRIs or placebos for three weeks and were subjected to a relearning programme with new face pairs and character-word pairs. A third measurement at the end concluded the study.

The researchers' hypothesis was confirmed: SSRIs cause new connections to be stored more easily, as evidenced by the visible changes in the brain. “The increase in neuroplasticity is an essential mechanism in the action of SSRIs,” notes Rupert Lanzenberger. SSRIs switch the brain back to being receptive for new connections and facilitate the uncoupling of old ones. “Ultimately, the therapy of depression also seems to be about disconnecting acquired connections and gaining something like a new perspective on the world,” is how Lanzenberger describes it, and he adds: “We see that medication for depression is often only the first step. What is also important is the accompanying psychotherapy and experiencing new environmental stimuli, and this process can also be seen as a kind of relearning under increased plasticity.”

The study clearly demonstrated the increased neuroplasticity when SSRIs were administered in comparison to the control group: “In the imaging data, we were able to detect a different balance. Some areas are inhibited more than others and the balance between different brain areas changes, as does the intensity of the communication between the brain areas.” While SSRIs do not have a direct acute impact on a person’s mood, they change the susceptibility to relearning processes and thus help people to find their way out of depression under favourable conditions. This insight can be used for other substances that increase neuroplasticity and could have a faster antidepressant effect.

Rupert Lanzenberger is an associate professor of neuroscience and a physician at the Department of Psychiatry and Psychotherapy at the Medical University of Vienna, where he has been heading the NeuroimagingLab since 2005. He works with imaging techniques in order to visualise molecular and functional processes in the brain, especially in psychiatric diseases and in the field of psychopharmacology. Lanzenberger has received numerous international research awards and is a member of the European Academy of Sciences and Arts (EASA).

Publications

Reed MB, Vanicek T, Seiger R, et al: Neuroplastic effects of a selective serotonin reuptake inhibitor in relearning and retrieval, in: NeuroImage 2021

Spurny B, Vanicek T, Seiger R, et al.: Effects of SSRI treatment on GABA and glutamate levels in an associative relearning paradigm, in: NeuroImage 2021

Spurny B, Seiger R, Moser P, et al: Hippocampal GABA levels correlate with retrieval performance in an associative learning paradigm, in: NeuroImage 2020